Stochastic Nanoroughness Inhibits and Reverses Glial Scarring In Vitro and In Vivo via a Mechanobiology Paradigm Involving Piezo-1

Physical insult to the central nervous system (CNS) such as during electrode insertion leads to reactive astrogliosis which in turn contributes to glial scarring (GS). To date, reducing GS in these settings has focused on pharmacological agents and variations in electrode material composition or implantation procedures, and the role of electrode surface topography has remained unexplored. Since proteoglycans, a major component of GS tissue, possesses very well-defined (nano) topography, a role for stochastic nanoroughness in glial scar formation is theorized. Using an in vitro system, we provide proof of concept that on substrates possessing stochastic nanoroughness corresponding to that of healthy astrocytes, glial scar formation is significantly inhibited, and more importantly, can be even reversed, and it involves signaling via the stretch-activated cation channel Piezo-1. In vivo studies reveal an absence of astrocytes aggregation along the electrode track of chronically implanted electrodes modified with stochastic surface nanoroughness, compared to non-modified electrodes, while signal detection within the superior colliculus remains unaffected. These findings shedlight on the crucial role of stochastic biophysical cues in modulating GS formation; and offer a promising non-chemical approach for engineering neural biomaterials interface for the CNS.